title: Reversal of p-glycoprotein-mediated multidrug resistance by macrocyclic bisbibenzyl derivatives in adriamycin-resistant human myelogenous leukemia (K562/A02) cells.
abstract: Macrocyclic bisbibenzyls, a class of characteristic natural molecules derived from liverworts, have diverse biological significances. Dihydroptychantol A (DHA) was identified to be an antifungal active macrocyclic bisbibenzyl from liverwort Asterella angusta. In an attempt to understand other biological activities of this compound, the chemical synthesized DHA and its analogues (compounds 1-3) were employed to test this possibility by using adriamycin-resistant K562/A02 cells. Among the tested compounds (1-4), DHA showed the strongest potency to increase adriamycin cytotoxicity toward K562/A02 cells by MTT assays and its reversal fold is 8.18 (20 microM). Mechanisms of DHA on p-glycoprotein (P-gp)-mediated multidrug resistance (MDR) were further investigated. Based on the flow cytometry, we detected the significant increase of adriamycin and rhodamine123 accumulation in K562/A02 cells exposed to various concentrations of DHA, meanwhile, notable decrease of rhodamine123 efflux was also observed, which revealed DHA caused a decline of P-gp activity. Furthermore, P-gp expression was analyzed by the flow cytometry and RT-PCR. Dose-dependent reduction of P-gp expression was measured in K562/A02 cells pretreated with DHA for 24h. No such results were found in parental K562 cells. These results demonstrated DHA reversed effectively MDR by blocking the drugs to be pumped out via inhibiting P-gp function and expression pathway.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Wenhua West Road 44, Jinan 250012, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Zhu
authors.forename: Hui-Qing
authors.initials: HQ
authors.lastname: Yuan
authors.forename: Yan-Qiu
authors.initials: YQ
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Shuang-Jing
authors.initials: SJ
authors.lastname: Li
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Lou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D035926:Hepatophyta / Q000737:chemistry; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010647:Phenyl Ethers / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D010647:Phenyl Ethers; D012333:RNA, Messenger; D013267:Stilbenes; C539241:dihydroptychantol A; D020112:Rhodamine 123; D004317:Doxorubicin